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Chemical compound
Gaboxadol , also known as 4,5,6,7-t etrah ydroi soxazolo(5,4-c)p yridin-3-ol (THIP ), is a conformationally constrained derivative of the
alkaloid
muscimol that was first synthesized in 1977 by the Danish
chemist Poul Krogsgaard-Larsen.
[1] In the early 1980s gaboxadol was the subject of a series of
pilot studies that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for
tardive dyskinesia ,
Huntington's disease ,
Alzheimer's disease , and
spasticity .
[1] It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "
adverse effect " for the treatment of insomnia, resulting in a series of clinical trials sponsored by
Lundbeck and
Merck .
[1]
[2] In March, 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the
GABA system, but in a different way from
benzodiazepines ,
Z-Drugs , and
barbiturates . Lundbeck states that gaboxadol also increases
deep sleep (stage 4). Unlike
benzodiazepines , gaboxadol does not demonstrate
reinforcement in mice or baboons despite activation of
dopaminergic neurons in the
ventral tegmental area .
[3]
In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan is to develop it for
FXS and
Angelman syndrome .
[4] It is known internally in Ovid as OV101 .
Pharmacology
Gaboxadol is a supra-maximal agonist at α4β3δ GABAA receptors, low-potency agonist at α1β3γ2, and partial agonist at α4β3γ.
[5]
[6] Its affinity for this α4-containing subtype of the GABAA receptor is 10× greater than other non-α4 containing subtypes.
[7] Gaboxadol also has a unique affinity for extrasynaptic GABAA receptors, which desensitize more slowly and less extensively than synaptic GABAA receptors.
[8]
See also
References
^
a
b
c Morris H (August 2013).
"Gaboxadol" . Harper's Magazine . Retrieved 2014-11-20 .
^
US 4278676 , Krogsgaard-Larsen P, "Heterocyclic compounds", issued 14 July 1981, assigned to H Lundbeck AS
^ Vashchinkina E, Panhelainen A, Vekovischeva OY, Aitta-aho T, Ebert B, Ator NA, et al. (April 2012).
"GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons" . The Journal of Neuroscience . 32 (15): 5310–20.
doi :
10.1523/JNEUROSCI.4697-11.2012 .
PMC
6622081 .
PMID
22496576 .
^ Tirrell M (16 April 2015).
"Former Teva CEO's new gig at Ovid Therapeutics" . CNBC. Retrieved 2015-05-06 .
^ Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA (August 2002).
"Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors" . British Journal of Pharmacology . 136 (7): 965–974.
doi :
10.1038/sj.bjp.0704795 .
PMC
1573424 .
PMID
12145096 .
^ Orser BA (2006-04-15).
"Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs" . Journal of Clinical Sleep Medicine . 02 (2).
doi :
10.5664/jcsm.26526 .
ISSN
1550-9389 .
^ Rudolph U, Knoflach F (July 2011).
"Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes" . Nature Reviews. Drug Discovery . 10 (9): 685–697.
doi :
10.1038/nrd3502 .
PMC
3375401 .
PMID
21799515 .
^ Orser BA (April 2006). "Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs". Journal of Clinical Sleep Medicine . 2 (2): S12–8.
doi :
10.5664/jcsm.26526 .
PMID
17557502 .
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